Understanding Cellular Heterogeneity in Cancer

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Tumors are composed of societies of cells in which the phenotype, or state, of each tumor cell is influenced by multiple cell-autonomous and cell-extrinsic factors. The diversity of these cellular states poses a challenge for effective cancer therapies. Our group is interested in a variety of biological questions pertaining to cellular heterogeneity in solid tumors:

Uncovering the Biological Basis of Tumor Heterogeneity

The selective advantage for the establishment and, more interestingly, the maintenance of heterogeneity in tumors is unclear. Our results indicate that tumors benefit collectively from protecting cellular health of a subpopulation of stem-like cancer cells at the expense of other cells, much like normal-tissue stem cells. Therefore the stem-like cells likely exhibit a distinct gene expression program that is compatible with stem-like properties such as unlimited replicative potential and improved control of cellular stress. To test this hypothesis, our laboratory will utilize lineage tracing, a fate-mapping technique that relies on the targeted introduction of heritable genetic marks into distinct cell subpopulations in situ within established genetically engineered murine tumors.

Elucidating Signaling Pathways that Maintain the Niche for Stem-Like Cells in Cancer

We believe that uncovering pathways controlling of stem-like cell and niche cell phenotypes in cancer can be leveraged to develop conceptually novel therapies for patients. In particular, our laboratory will focus on the niche cells that provide the Wnt signal, and possibly also other signals, as they have not been previously studied in solid tumors. Importantly, these cells are the master regulators of the stem-like phenotype. Our group will elucidate the molecular mechanisms that determine the niche cell fate, which may prove to be useful therapeutic targets in cancer therapy.

Implications of Reducing Intratumoral Heterogeneity for Cancer

Cellular phenotypic heterogeneity, an important hallmark of cancer, poses a significant hurdle for cancer therapy. A central tenet of the laboratory will be to utilize genetically engineered mouse models to functionally test strategies emerging from single-cell transcriptomics data to reduce cellular heterogeneity in tumors. These approaches will include use of somatic genome editing, CRISPR-mediated gene activation as well as utilizing small molecules where appropriate. The outcomes of such perturbations will be tested by classical histopathological and gene expression analyses, as well as by single-cell transcriptomics. These analyses will allow us to directly test the impact of stem-like or niche cell depletion on tumor heterogeneity, as well as to identify populations that are intrinsically more sensitive to standard chemotherapies or targeted therapies. This information will be used to uncover pathways that maintain phenotypic heterogeneity in tumors, which can be leveraged to force cancer cells into states that are more sensitive to therapy.